Targeting Extracellular Heat Shock Protein 70 Ameliorates Doxorubicin‐Induced Heart Failure Through Resolution of Toll‐Like Receptor 2–Mediated Myocardial Inflammation

Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease

Ke Li¹  Xiao‐Wei Zhang²  Peng Liu²  Ji‐Chao Zhou²  Hua‐Yan Bao²  Xiao‐Xi Lv²  Cai‐Cai Jin²  Fang Hua²  Bing Cui²  Zhuo‐Wei Hu² 

[1] Institute of Medicinal Biotechnology Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China;Molecular Immunology and Pharmacology Group State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia Medica Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China;

关键词: cardiac dysfunction;    cardiac remodeling;    damage‐associated molecular patterns;    nuclear factor‐κB;    toll‐like receptor;   

DOI  :  10.1161/JAHA.119.012338

来源: DOAJ

【 摘 要 】

Background Heart failure (HF) is one of the most significant causes of morbidity and mortality for the cardiovascular risk population. We found previously that extracellular HSP70 (heat shock protein) is an important trigger in cardiac hypertrophy and fibrosis, which are associated with the development of heart dysfunction. However, the potential role of HSP70 in response to HF and whether it could be a target for the therapy of HF remain unknown. Methods and Results An HF mouse model was generated by a single IP injection of doxorubicin at a dose of 15 mg/kg. Ten days later, these mice were treated with an HSP70 neutralizing antibody for 5 times. We observed that doxorubicin treatment increased circulating HSP70 and expression of HSP70 in myocardium and promoted its extracellular release in the heart. Blocking extracellular HSP70 activity by its antibody significantly ameliorated doxorubicin‐induced left ventricular dilation and dysfunction, which was accompanied by a significant inhibition of cardiac fibrosis. The cardioprotective effect of the anti‐HSP70 antibody was largely attributed to its ability to promote the resolution of myocardial inflammation, as evidenced by its suppression of the toll‐like receptor 2–associated signaling cascade and modulation of the intracellular distribution of the p50 and p65 subunits of nuclear factor‐κB. Conclusions Extracellular HSP70 serves as a noninfectious inflammatory factor in the development of HF, and blocking extracellular HSP70 activity may provide potential therapeutic benefits for the treatment of HF.

【 授权许可】

Unknown